DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, a therapeutic composition comprising a carbon-nitride dot nanocarrier, claims 1-9, 14, and 15 in the reply filed on 7/10/2025 is acknowledged. Claims 10-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/10/2025.
Priority
Priority to 62/931,594, filed 11/6/2019 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 5/6/2022 before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-3 and 5-16, filed 10/28/2025, are currently pending. Claim 4 is canceled. Claims 10-13 are withdrawn. Claim 4 is canceled. Claim 16 is new.
Claim Interpretation
To facilitate compact prosecution, the claims will be interpreted in accordance with the statement provided by Applicant Reply, filed 10/28/2025, page 4, para. 2: “If the Office is proposing that the dendrimer of Baker would have doxorubicin, transferrin, and the carbon-nitride dot of Liu all separately attached, this would not meet the requirement of the instant claims that the doxorubicin and transferrin are cross-linked to the carbon-nitride dot.”
Because of this, claim 16 is interpreted to have the same scope as claim 14.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 5-9, and 14-15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, claim 1 recites: “A therapeutic composition comprising a carbon-nitride dot nanocarrier having a surface comprising carbodiimide cross-linked doxorubicin and transferrin thereupon.”
It is not clear whether both the doxorubicin and nitride dot must both be carbodiimide cross-linked to the carbon-nitride dot or whether only the doxorubicin need be cross-linked. Clarification is required.
Regarding claims 2-3 and 5-9, none of these claims resolve the indefiniteness of claim 1 and therefore are rejected.
Regarding claim 14, claim 14 recites: “A therapeutic composition comprising a carbon-nitride dot nanocarrier having a surface comprising cross-linked doxorubicin and a single-chain variable fragment(scFv) against transferrin receptor 1 (anti-TFR1 scFv) thereupon.”
It is not clear whether both the doxorubicin and scFV must both be carbodiimide cross-linked to the carbon-nitride dot or whether only the doxorubicin need be cross-linked. Clarification is required.
Regarding claim 15, this claim does not resolve the indefiniteness of claim 14 and therefore is rejected.
Regarding claim 16, this claim is not rejected because it clarifies the indefiniteness of claim 14. Note that for examination purposes, because of the above claim interpretation, this claim has the same scope as claim 14.
Previous Rejections
Specification
Response to Arguments
The specification was previously objected to for using tradenames without proper notation. Such terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Applicant’s arguments, see Applicants Remarks, page 1, para. 5, filed 10/28/2025, with respect to the specification have been fully considered and are persuasive. The objection to the specification has been withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Response to Arguments
Applicant’s arguments, see Applicants Remarks, page 1, para. 6, filed 10/28/2025, with respect to the specification have been fully considered and are persuasive. The rejection of claim 4 has been rendered moot because claim 4 is currently canceled.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Response to Arguments
Claims 1-9 were previously rejected under 35 U.S.C. 103 as being unpatentable over Baker et al. US2012/0259098 A1 in view of Liu et al. (Liu, et al. Journal of Materials Chemistry B 7.36:5432-5448 (2019)).
Applicant’s arguments, see Applicants Remarks, page 1, para. 7, filed 10/28/2025, with respect to the rejection of claims 1-3 and 5-9 under U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. Claim 4 has been canceled, making this rejection moot. However, upon further consideration, a new ground) of rejection is made as described below.
Claims 14 and 15 were previously rejected under 35 U.S.C. 103 as being unpatentable over Baker et al. US2012/0259098 A1 in view of Liu et al. (Liu, et al. Journal of Materials Chemistry B 7.36:5432-5448 (2019)) as applied to claim 1 above, and further in view of Tortorella et al. (Tortorella, et al. The Journal of membrane biology 247.4): 291-307 (2014)) and Daniels-Wells et al. (Daniels-Wells et al. Immunotherapy 8.9: 991-994 (2016)).
Applicant’s arguments, see Applicants Remarks, page 5, para. 2, filed 10/28/2025, with respect to the rejection of claims 14 and 15 under U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made as described below.
New Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Kratz et al. (Kratz, et al. Journal of pharmaceutical sciences 87.3: 338-346 (1998) in view of Liu et al. (Liu, et al. Journal of Materials Chemistry B 7.36: 5432-5448 (2019)), Chen, et al. (Chen, et al. Advanced Functional Materials 27.39: 1702695 (2017)) and Choi et al. (Choi, et al. Cutting-edge enabling technologies for regenerative medicine : 161-210(2018)).
Regarding claim 1, claim 1 recites: “A therapeutic composition comprising a carbon- nitride dot nanocarrier having a surface comprising carbodiimide cross-linked doxorubicin and transferrin thereupon.”
Kratz discloses a conjugate of doxorubicin and transferrin:
“Due to our interest in the role which natural plasma proteins play in the in vivo distribution of anticancer drugs, we have developed doxorubicin conjugates of the
serum protein transferrin, the iron(III) transport protein. Besides the fact that transferrin has a molecular weight of 80 000, which is suitable for the above concept of passive tumor targeting, this serum protein is suitable as a potential drug delivery system for the following reasons:
(a) Transferrin exhibits a significant uptake in tumor
tissue due to high amounts of specific transferrin receptors
(150 000-1 000 000 per cell) on the cell surface of tumor
cells.
(b) It is a stable, commercially available protein, which
has been intensively studied and characterized.
(c) Transferrin has been used as a drug delivery system
for toxins and DNA.”
(Kratz et al., page 338, col. 2, para. 3).
Kratz does not disclose the case wherein the doxorubicin and transferrin are conjugated to a carbon nitride dot via carbodiimide crosslinks.
However, Liu discloses the usage of carbon nitride quantum dots for biomedical applications:
“In comparison with traditional semiconductor quantum dots, the g-CNQDs demonstrate low cytotoxicity and good biosafety due to their metal-free properties and easy functionalization. In addition, the g-CNQDs also demonstrate superior optical properties including excitation-wavelength-tunable PL emission, photostability and high quantum yield over the organic dyes and carbon-based QDs. Meanwhile, the smaller size distribution (<20 nm) and good stability endow g-CNQDs with rapid metabolism and excellent biocompatibility. The highly p-conjugated electronic structures and functional surface groups enable g-CNQDs as highly efficient nanocarriers for targeted molecule and anti-cancer drug loading.
Based on their unique structure and intrinsic properties, the g-CNQDs have great potential to meet the requirement of next generation biomaterials for clinical use.” (Liu et al., page 5438, col. 2, para. 2).
Liu also discloses carbon nitride quantum dots with carboxylic acid groups:
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652
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(Liu et al., page 5438, Fig. 9)
Furthermore, Chen discloses that carbon nitride quantum dots can be functionalized with either an NH2 group or COOH group for the purpose of carbodiimide crosslinking:
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788
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(Chen et al., page 4, Fig. 4).
“The inherent amino-groups on g-CN nanostructures enable them to be coupled with metal complexes to form chelate bonds, or conjugated with any amino acid, peptide, protein antibody, nucleic acid, or another nanoparticle that carries a carboxylic acid group using carbodiimide coupling chemistry. The same method applies to the conjugation of carboxyl-g-CN nanostructures to amino-bearing molecules or materials.” (Chen et al., page 5, col. 2, para. 2).
Choi et al. discusses the usage of carbodiimide crosslinking:
“To solve this limitations, covalent binding has been employed, which offers stable attachment of biomolecules to engineered scaffolds. It was proved that covalent immobilization is a very efficient approach to guide the release profile of the conjugate molecules at desirable site.
Carbodiimide system is widely adopted in protein-based materials to react activated surface carboxylic acid groups with the amines existed on the peptide. Carboxylic groups are activated through 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) with either N-hydroxysuccinimide (NHS) or dicyclohexyl-carboiimide (DCC) or carbonyl diimidazole (CDI).” (Choi et al, page 170, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the doxorubicin-transferrin conjugate of Kratz with the carbon nitride quantum dot of Liu using carbodiimide crosslinking as described by Chen and Choi to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to make this combination for at least two reasons. First, Liu discloses the usage of carbon nitride quantum dots for cancer therapy: “Due to their unique structure feature including high surface area, abundant conjugate structure, and good biocompatibility, the g-CNQDs have been considered as an ideal candidate for a potential drug delivery system.” (Liu et al., page 5443, col. 2, para. 3). Also, Liu discloses that carbon nitride quantum dots can be used for bioimaging, which can be used to track the localization of the therapeutic: “Therefore, the rational design and synthesis of stable PL probes for FOI is the most significant issue. In recent years, the g-CNQDs have served as an optical marker to replace traditional QDs and organic dyes due to their tunable fluorescence emission, high quantum yield, low toxicity, good biocompatibility, and resistance to photobleaching.” (Liu et al., page 5442, col. 2, para. 2).
Regarding the usage of carbodiimide crosslinking, a person of ordinary skill in the art would use carbodiimide crosslinking as disclosed by Chen and Choi in order to take advantage of the “very efficient approach to guide the release profile of the conjugate molecules at desirable site”. (Choi et al, page 170, col. 2, para. 2).
Regarding the doxorubicin and transferrin both being crosslinked to the carbon nitride quantum dot, this is obvious because a finite number of ways exist to arrange three elements. Furthermore, both doxorubicin and transferrin have NH2 moieties, making a COOH functionalized carbon nitride quantum dot as disclosed by Chen above an obvious possibility for connection.
A person of ordinary skill in the art would have a reasonable expectation of success because Kratz discloses that: “These observations confirm earlier work by Faulk et al.,
who showed that his transferrin conjugates of doxorubicin bind to the transferrin receptor and are cytotoxic without intercalating nuclear DNA.” (Kratz et al., page 345, col. 1, para. 1). Furthermore, Liu discloses that carbon nitride quantum dots have already been used in chemotherapies: “So far, two examples of g-CNQD-based nanocarriers have been developed for responsive drug release and chemotherapy.” (page 5443, col. 2, para. 3). Lastly, Choi discloses that the carbodiimide linking method is widely used in the world of functionalization: “Carbodiimide system is widely adopted in protein-based materials to react activated surface carboxylic acid groups with the amines existed on the peptide”. (Choi et al, page 170, col. 2, para. 2). Based on these disclosures a person of ordinary skill in the art would reasonably expect a carbon nitride quantum dot-doxorubicin-transferrin conjugate to bind to transferrin receptor and possesses a desirable release profile because of the carbodiimide linkage.
Consequently, claim 1 is obvious over Kratz et al. in view of Liu et al., Chen et al., and Choi et al. and rejected.
Claims 2, 3, and 5-9 are rejected under 35 U.S.C. 103 as being unpatentable over Kratz et al. (Kratz, et al. Journal of pharmaceutical sciences 87.3: 338-346 (1998) in view of Liu et al. (Liu, et al. Journal of Materials Chemistry B 7.36: 5432-5448 (2019)), Chen, et al. (Chen, et al. Advanced Functional Materials 27.39: 1702695 (2017)), Choi et al. (Choi, et al. Cutting-edge enabling technologies for regenerative medicine : 161-210(2018)), and Merli et al. (Merli,et al. Leukemia & lymphoma 53.4: 581-588 (2012)).
Regarding claim 2, claim 2 recites a therapeutic composition comprising rituximab, cyclophosphamide, vincristine, prednisone, transferrin, and doxorubicin, wherein the doxorubicin and transferrin is a carbodiimide cross-linked doxorubicin and transferrin on the surface of a carbon-nitride dot nanocarrier.
Merli discloses the combination of rituximab, cyclophosphamide, vincristine, prednisone, transferrin, and doxorubicin in a clinical setting:
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(Merli et al., page 582, Table 1).
Merli also discloses that this is a common drug combination: “This randomized trial was designed to compare the efficacy of standard R-CHOP with a less intense regimen (R-mini-
CEOP) for the treatment of elderly patients with DLBCL prospectively defined as “fit ” at CGA assessment.” (Merli et al., page 585, col. 2, para. 2).
Merli shows that R-CHOP treatment is efficacious:
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791
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(Merli et al., page 585, Fig. 2).
Kratz discloses a conjugate of doxorubicin and transferrin:
“Due to our interest in the role which natural plasma proteins play in the in vivo distribution of anticancer drugs, we have developed doxorubicin conjugates of the
serum protein transferrin, the iron(III) transport protein. Besides the fact that transferrin has a molecular weight of 80 000, which is suitable for the above concept of passive tumor targeting, this serum protein is suitable as a potential drug delivery system for the following reasons:
(a) Transferrin exhibits a significant uptake in tumor
tissue due to high amounts of specific transferrin receptors
(150 000-1 000 000 per cell) on the cell surface of tumor
cells.
(b) It is a stable, commercially available protein, which
has been intensively studied and characterized.
(c) Transferrin has been used as a drug delivery system
for toxins and DNA.”
(Kratz et al., page 338, col. 2, para. 3).
Kratz does not disclose the case wherein the doxorubicin and transferrin are conjugated to a carbon nitride dot via carbodiimide crosslinks.
However, Liu discloses the usage of carbon nitride quantum dots for biomedical applications:
“In comparison with traditional semiconductor quantum dots, the g-CNQDs demonstrate low cytotoxicity and good biosafety due to their metal-free properties and easy functionalization. In addition, the g-CNQDs also demonstrate superior optical properties including excitation-wavelength-tunable PL emission, photostability and high quantum yield over the organic dyes and carbon-based QDs. Meanwhile, the smaller size distribution (<20 nm) and good stability endow g-CNQDs with rapid metabolism and excellent biocompatibility. The highly p-conjugated electronic structures and functional surface groups enable g-CNQDs as highly efficient nanocarriers for targeted molecule and anti-cancer drug loading.
Based on their unique structure and intrinsic properties, the g-CNQDs have great potential to meet the requirement of next generation biomaterials for clinical use.” (Liu et al., page 5438, col. 2, para. 2).
Liu also discloses carbon nitride quantum dots with carboxylic acid groups:
PNG
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351
652
media_image1.png
Greyscale
(Liu et al., page 5438, Fig. 9)
Furthermore, Chen discloses that carbon nitride quantum dots can be functionalized with either an NH2 group or COOH group for the purpose of carbodiimide crosslinking:
PNG
media_image2.png
450
788
media_image2.png
Greyscale
(Chen et al., page 4, Fig. 4).
“The inherent amino-groups on g-CN nanostructures enable them to be coupled with metal complexes to form chelate bonds, or conjugated with any amino acid, peptide, protein antibody, nucleic acid, or another nanoparticle that carries a carboxylic acid group using carbodiimide coupling chemistry. The same method applies to the conjugation of carboxyl-g-CN nanostructures to amino-bearing molecules or materials.” (Chen et al., page 5, col. 2, para. 2).
Choi et al. discusses the usage of carbodiimide crosslinking:
“To solve this limitations, covalent binding has been employed, which offers stable attachment of biomolecules to engineered scaffolds. It was proved that covalent immobilization is a very efficient approach to guide the release profile of the conjugate molecules at desirable site.
Carbodiimide system is widely adopted in protein-based materials to react activated surface carboxylic acid groups with the amines existed on the peptide. Carboxylic groups are activated through 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) with either N-hydroxysuccinimide (NHS) or dicyclohexyl-carboiimide (DCC) or carbonyl diimidazole (CDI).” (Choi et al, page 170, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the drug combination of Merli and substitute the conjugate of Kratz, Liu, and Choi which is made by combining the doxorubicin-transferrin conjugate of Kratz with the carbon nitride quantum dot of Liu using carbodiimide crosslinking as described by Chen and Choi to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use this drug combination because Merli shows that this drug combination is efficacious. (Merli et al., page 585, Fig. 2).
Regarding the carbon nitride quantum dot-doxorubicin-transferrin conjugate, Liu discloses the usage of carbon nitride quantum dots for cancer therapy: “Due to their unique structure feature including high surface area, abundant conjugate structure, and good biocompatibility, the g-CNQDs have been considered as an ideal candidate for a potential drug delivery system.” (Liu et al., page 5443, col. 2, para. 3). Also, Liu discloses that carbon nitride quantum dots can be used for bioimaging, which can be used to track the localization of the therapeutic: “Therefore, the rational design and synthesis of stable PL probes for FOI is the most significant issue. In recent years, the g-CNQDs have served as an optical marker to replace traditional QDs and organic dyes due to their tunable fluorescence emission, high quantum yield, low toxicity, good biocompatibility, and resistance to photobleaching.” (Liu et al., page 5442, col. 2, para. 2).
Regarding the usage of carbodiimide crosslinking, a person of ordinary skill in the art would use carbodiimide crosslinking as disclosed by Chen and Choi in order to take advantage of the “very efficient approach to guide the release profile of the conjugate molecules at desirable site”. (Choi et al, page 170, col. 2, para. 2).
Regarding the doxorubicin and transferrin both being crosslinked to the carbon nitride quantum dot, this is obvious because a finite number of ways exist to arrange three elements. Furthermore, both doxorubicin and transferrin have NH2 moieties, making a COOH functionalized carbon nitride quantum dot as disclosed by Chen above an obvious possibility for connection.
A person of ordinary skill in the art would have a reasonable expectation of success because this drug combination is already shown to be efficacious by Merli (Merli et al., page 585, Fig. 2).
Regarding the carbon nitride quantum dot conjugate, Kratz discloses that: “These observations confirm earlier work by Faulk et al., who showed that his transferrin conjugates of doxorubicin bind to the transferrin receptor and are cytotoxic without intercalating nuclear DNA.” (Kratz et al., page 345, col. 1, para. 1). Furthermore, Liu discloses that carbon nitride quantum dots have already been used in chemotherapies: “So far, two examples of g-CNQD-based nanocarriers have been developed for responsive drug release and chemotherapy.” (page 5443, col. 2, para. 3). Lastly, Choi discloses that the carbodiimide linking method is widely used in the world of functionalization: “Carbodiimide system is widely adopted in protein-based materials to react activated surface carboxylic acid groups with the amines existed on the peptide”. (Choi et al, page 170, col. 2, para. 2). Based on these disclosures a person of ordinary skill in the art would reasonably expect a carbon nitride quantum dot-doxorubicin-transferrin conjugate to bind to transferrin receptor and possesses a desirable release profile because of the carbodiimide linkage.
Consequently, claim 2 is obvious over Kratz et al. in view of Liu et al., Chen et al., Choi et al., and Merli et al. and rejected.
Regarding claim 3, claim 2 is rejected as described above. Claim 3 further recites the case wherein the composition contains triazine rings (C3N4). Liu discloses: “ Among all five allotropes of known C3N4 (including α-C3N4, β-C3N4, graphitic-C3N4 (g-C3N4), pseudocubic-C3N4 and cubic-C3N4), g-C3N4 is the most popular research direction because the structure of triazine in g-C3N4 is more advantageous for thermodynamic stability.” (page 5433, col. 1, para. 2).
Consequently, claim 3 is obvious over Kratz et al. in view of Liu et al., Chen et al., Choi et al., and Merli et al. and rejected.
Regarding claim 5, claim 2 is rejected as described above. Claim 5 further recites the case wherein the nanocarrier contains amine groups, amide groups, and carboxyl groups on its surface. Liu discloses: “The g-CNQDs were covalently linked to 4-amino-2,2,6,6-tetramethyl(piperidin-1-yl)oxyl (4-AT) via an amide bond to produce the g-CNQDs–4-AT complex.” (Liu et al., page 5440, col. 1, para. 1) and “The as-obtained g-CNQDs with a diameter range from 1 nm to 5 nm were highly dispersible in water due to the abundance of hydroxyl, carboxylic acid, and amine groups on the surface of g-CNQDs.” (Liu et al., page 5435, col. 1, para. 2).
Furthermore, Chen discloses: “The inherent amino-groups on g-CN nanostructures enable them to be coupled with metal complexes to form chelate bonds, or conjugated with any amino acid, peptide, protein antibody, nucleic acid, or another nanoparticle that carries a carboxylic acid group using carbodiimide coupling chemistry. The same method applies to the conjugation of carboxyl-g-CN nanostructures to amino-bearing molecules or materials.” (Chen et al., page 5, col. 2, para. 2). After a carbodiimide reaction discussed above as being obvious, the surface of the carbon nitride quantum dot will also necessarily have amide groups on its surface because that is the end product of the carbodiimide crosslinking reaction.
Consequently, claim 5 is obvious over Kratz et al. in view of Liu et al., Chen et al., Choi et al., and Merli et al. and rejected.
Regarding claim 6, claim 2 is rejected as described above. Claim 6 further recites the case wherein the nanocarrier has an excitation wavelength between 450 - 600 nm. Liu discloses: “After being incubated for 24 h, the g-CNQD-treated HEK 293T cell can demonstrate bright blue, green, and red fluorescence emission in multi-color form under 405, 488, and 543 nm excitation, respectively, as shown in Fig. 19.” (Liu et al., page 5443, col. 1, para. 3). MPEP 2131.03(I) recites: “"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (citing In re Petering, 301 F.2d 676, 682, 133 USPQ 275, 280 (CCPA 1962)).”
Consequently, claim 6 is obvious over Kratz et al. in view of Liu et al., Chen et al., Choi et al., and Merli et al. and rejected.
Regarding claim 7, claim 2 is rejected as described above. Claim 7 further recites the case where the composition has a potency against diffuse large B-cell lymphoma in vitro that is 10 - 100 fold greater than doxorubicin treatment alone. MPEP 2112.01(II) states: “"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable.” The composition of claim 2 will necessarily have this claimed property because the structure confers this property.
Consequently, claim 7 is obvious over Kratz et al. in view of Liu et al., Chen et al., Choi et al., and Merli et al. and rejected.
Regarding claim 8, claim 2 is rejected as described above. Claim 8 further recites the case where the composition has an LD5o to diffuse large B-cell lymphoma that is less than 100 nm. MPEP 2112.01(II) states: “"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable.” The composition of claim 2 will necessarily have this claimed property because the structure confers this property.
Consequently, claim 8 is obvious over Kratz et al. in view of Liu et al., Chen et al., Choi et al., and Merli et al. and rejected.
Regarding claim 9, claim 2 is rejected as described above. Claim 9 further recites the case where the carbodiimide cross-linked doxorubicin and transferrin have increased in vivo efficacy. MPEP 2112.01(II) states: “"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable.” The composition of claim 2 will necessarily have this claimed property because the structure confers this property.
Consequently, claim 9 is obvious over Kratz et al. in view of Liu et al., Chen et al., Choi et al., and Merli et al. and rejected.
Claims 14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Kratz et al. (Kratz, et al. Journal of pharmaceutical sciences 87.3: 338-346 (1998) in view of Liu et al. (Liu, et al. Journal of Materials Chemistry B 7.36: 5432-5448 (2019)), Chen, et al. (Chen, et al. Advanced Functional Materials 27.39: 1702695 (2017)), Choi et al. (Choi, et al. Cutting-edge enabling technologies for regenerative medicine : 161-210(2018)), and Neiveyans et al. (Neiveyans, et al. MAbs. Vol. 11. No. 3. Taylor & Francis, (2019)).
Regarding claim 1, claim 1 recites: “A therapeutic composition comprising a carbon- nitride dot nanocarrier having a surface comprising carbodiimide cross-linked doxorubicin and transferrin thereupon.”
Kratz discloses a conjugate of doxorubicin and transferrin:
“Due to our interest in the role which natural plasma proteins play in the in vivo distribution of anticancer drugs, we have developed doxorubicin conjugates of the
serum protein transferrin, the iron(III) transport protein. Besides the fact that transferrin has a molecular weight of 80 000, which is suitable for the above concept of passive tumor targeting, this serum protein is suitable as a potential drug delivery system for the following reasons:
(a) Transferrin exhibits a significant uptake in tumor
tissue due to high amounts of specific transferrin receptors
(150 000-1 000 000 per cell) on the cell surface of tumor
cells.
(b) It is a stable, commercially available protein, which
has been intensively studied and characterized.
(c) Transferrin has been used as a drug delivery system
for toxins and DNA.”
(Kratz et al., page 338, col. 2, para. 3).
Kratz does not disclose the case wherein the doxorubicin is conjugated to a carbon nitride dot via carbodiimide crosslinks and an anti-TFR1 scFV is also conjugated to the carbon nitride dot. .
However, Liu discloses the usage of carbon nitride quantum dots for biomedical applications:
“In comparison with traditional semiconductor quantum dots, the g-CNQDs demonstrate low cytotoxicity and good biosafety due to their metal-free properties and easy functionalization. In addition, the g-CNQDs also demonstrate superior optical properties including excitation-wavelength-tunable PL emission, photostability and high quantum yield over the organic dyes and carbon-based QDs. Meanwhile, the smaller size distribution (<20 nm) and good stability endow g-CNQDs with rapid metabolism and excellent biocompatibility. The highly p-conjugated electronic structures and functional surface groups enable g-CNQDs as highly efficient nanocarriers for targeted molecule and anti-cancer drug loading.
Based on their unique structure and intrinsic properties, the g-CNQDs have great potential to meet the requirement of next generation biomaterials for clinical use.” (Liu et al., page 5438, col. 2, para. 2).
Liu also discloses carbon nitride quantum dots with carboxylic acid groups:
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(Liu et al., page 5438, Fig. 9)
Furthermore, Chen discloses that carbon nitride quantum dots can be functionalized with either an NH2 group or COOH group for the purpose of carbodiimide crosslinking:
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(Chen et al., page 4, Fig. 4).
“The inherent amino-groups on g-CN nanostructures enable them to be coupled with metal complexes to form chelate bonds, or conjugated with any amino acid, peptide, protein antibody, nucleic acid, or another nanoparticle that carries a carboxylic acid group using carbodiimide coupling chemistry. The same method applies to the conjugation of carboxyl-g-CN nanostructures to amino-bearing molecules or materials.” (Chen et al., page 5, col. 2, para. 2).
Choi et al. discusses the usage of carbodiimide crosslinking:
“To solve this limitations, covalent binding has been employed, which offers stable attachment of biomolecules to engineered scaffolds. It was proved that covalent immobilization is a very efficient approach to guide the release profile of the conjugate molecules at desirable site.
Carbodiimide system is widely adopted in protein-based materials to react activated surface carboxylic acid groups with the amines existed on the peptide. Carboxylic groups are activated through 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) with either N-hydroxysuccinimide (NHS) or dicyclohexyl-carboiimide (DCC) or carbonyl diimidazole (CDI).” (Choi et al, page 170, col. 2, para. 2).
Neiveyans et al. discloses several anti-TFR1 scFV capable of binding to the transferrin receptor, which is the same binding destination as the transferrin conjugate of Kratz: “We have recently obtained six rapidly internalized antagonistic competitive anti-TfR1 single-chain variable-fragment (scFv) antibodies by phage display.” (Nieveyans, et al., page 593, col. 2, para. 2).
Neiveyans discloses that their scFV constructs are capable of binding to the target of interest:
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(Neiveyans, et al. page 594, Fig. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the doxorubicin-transferrin conjugate of Kratz, substitute the scFV of Neiveyans for the transferrin protein, and then combine with the carbon nitride quantum dot of Liu using carbodiimide crosslinking as described by Chen and Choi to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to substitute an scFV of Neiveyans for the transferrin protein to take advantage of the inherent cytotoxicity of the Neiveyans scFV molecules: “After 5 days of incubation, H7-Fc and H7-IgG1 strongly decreased the viability of both cell lines (IC50 in the range of 0.1 μg/mL) (Neiveyans et al., page 595, col. 2, para. 2).
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(Neiveyans, et al., page 597, Fig. 3).
A person of ordinary skill in the art would combine the doxorubicin and the scFV with a carbon nitride quantum dot for at least two reasons. First, Liu discloses the usage of carbon nitride quantum dots for cancer therapy: “Due to their unique structure feature including high surface area, abundant conjugate structure, and good biocompatibility, the g-CNQDs have been considered as an ideal candidate for a potential drug delivery system.” (Liu et al., page 5443, col. 2, para. 3). Also, Liu discloses that carbon nitride quantum dots can be used for bioimaging, which can be used to track the localization of the therapeutic: “Therefore, the rational design and synthesis of stable PL probes for FOI is the most significant issue. In recent years, the g-CNQDs have served as an optical marker to replace traditional QDs and organic dyes due to their tunable fluorescence emission, high quantum yield, low toxicity, good biocompatibility, and resistance to photobleaching.” (Liu et al., page 5442, col. 2, para. 2).
Regarding the usage of carbodiimide crosslinking, a person of ordinary skill in the art would use carbodiimide crosslinking as disclosed by Chen and Choi in order to take advantage of the “very efficient approach to guide the release profile of the conjugate molecules at desirable site”. (Choi et al, page 170, col. 2, para. 2).
Regarding the doxorubicin and scFV both being crosslinked to the carbon nitride quantum dot, this is obvious because a finite number of ways exist to arrange three elements. Furthermore, both doxorubicin and transferrin have NH2 moieties, making a COOH functionalized carbon nitride quantum dot as disclosed by Chen above an obvious possibility for connection.
A person of ordinary skill in the art would have a reasonable expectation of success because Kratz discloses that: “These observations confirm earlier work by Faulk et al.,
who showed that his transferrin conjugates of doxorubicin bind to the transferrin receptor and are cytotoxic without intercalating nuclear DNA.” (Kratz et al., page 345, col. 1, para. 1). As shown above, Neiveyans discloses that their disclosed scFVs also bind the transferrin receptor (Neiveyans, et al. page 594, Fig. 1). This shows both transferrin and anti-TFR1 scFVs can both target the transferrin receptor.
Furthermore, Liu discloses that carbon nitride quantum dots have already been used in chemotherapies: “So far, two examples of g-CNQD-based nanocarriers have been developed for responsive drug release and chemotherapy.” (page 5443, col. 2, para. 3). Lastly, Choi discloses that the carbodiimide linking method is widely used in the world of functionalization: “Carbodiimide system is widely adopted in protein-based materials to react activated surface carboxylic acid groups with the amines existed on the peptide”. (Choi et al, page 170, col. 2, para. 2). Based on these disclosures a person of ordinary skill in the art would reasonably expect a carbon nitride quantum dot-doxorubicin-transferrin conjugate to bind to transferrin receptor and possesses a desirable release profile because of the carbodiimide linkage.
Consequently, claim 14 is obvious over Kratz et al. in view of Liu et al., Chen et al., Choi et al., and Neiveyans et al. and rejected.
Regarding claim 16, this claim has the same scope as claim 14 under the current interpretation and therefore is rejected for the same reasons as claim 14.
Claims 15 are rejected under 35 U.S.C. 103 as being unpatentable over Kratz et al. (Kratz, et al. Journal of pharmaceutical sciences 87.3: 338-346 (1998) in view of Liu et al. (Liu, et al. Journal of Materials Chemistry B 7.36: 5432-5448 (2019)), Chen, et al. (Chen, et al. Advanced Functional Materials 27.39: 1702695 (2017)), Choi et al. (Choi, et al. Cutting-edge enabling technologies for regenerative medicine : 161-210(2018)), and Neiveyans et al. (Neiveyans, et al. MAbs. Vol. 11. No. 3. Taylor & Francis, (2019)) as applied to claim 14 above, and further in view of Merli et al. (Merli,et al. Leukemia & lymphoma 53.4: 581-588 (2012).
Regarding claim 15, claim 14 is rejected as described above. Claim 15 recites: “A therapeutic composition comprising, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, wherein the doxorubicin is cross-linked doxorubicin of claim 14.”
Kratz et al., Liu et al., Chen et al., Choi et al., and Neiveyans et al do not disclose this combination of drugs.
However, Merli discloses the combination of rituximab, cyclophosphamide, vincristine, prednisone, transferrin, and doxorubicin in a clinical setting:
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(Merli et al., page 582, Table 1).
Merli also discloses that this is a common drug combination: “This randomized trial was designed to compare the efficacy of standard R-CHOP with a less intense regimen (R-mini-
CEOP) for the treatment of elderly patients with DLBCL prospectively defined as “fit ” at CGA assessment.” (Merli et al., page 585, col. 2, para. 2).
Merli shows that R-CHOP treatment is efficacious:
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(Merli et al., page 585, Fig. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the drug combination of Merli and substitute the conjugate of Kratz, Liu, Choi, and Neiveyans which is made by substituting the scFV of Neiveyans for the transferrin of Kratz and then combining the doxorubicin-scFV conjugate with the carbon nitride quantum dot of Liu using carbodiimide crosslinking as described by Chen and Choi to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use this drug combination because Merli shows that this drug combination is efficacious. (Merli et al., page 585, Fig. 2).
A person of ordinary skill in the art would have a reasonable expectation of success because this drug combination is already shown to be efficacious by Merli (Merli et al., page 585, Fig. 2).
Consequently, claim 15 is obvious over Kratz et al. in view of Liu et al., Chen et al., Choi et al., and Neiveyans et al., as applied to claim 14 above, further in view of Merli et al. and rejected.
Conclusion
No claim is allowed.
Claims 1-3, 5-9, and 14-16 are rejected.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654